Chronic intermittent ethanol exposure enhances NMDA-receptor-mediated synaptic responses and NMDA receptor expression in hippocampal CA1 region

Nelson, Thomas E.; Ur, C. L.; Gruol, Donna L.

doi:10.1016/j.brainres.2005.04.041

Cited by 71 publications

(75 citation statements)

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“…Alcohol alters synaptic transmission at NMDA synapses, which might disrupt cortical processing or the information the cortex relays to other brain regions, thereby playing an important role in ethanol-withdrawal behaviors. Previous studies of CIE-induced alterations were almost derived from the hippocampus of CIE rat (Kokka et al, 1993;Cagetti et al, 2003;Nelson et al, 2005), and it is important to elucidate the CIE-induced alterations of NMDA receptor in the cortical region in view of its role in ethanol-withdrawal seizures. First, we compared whether CIE-induced neuroadaptive increase of NMDA receptor subunit expression will occur in a similar pattern in hippocampus and cortex.…”

Section: Discussionmentioning

confidence: 99%

“…1). Furthermore, to test whether this effect was long-lasting in cultured cortical neurons like that described in the changes of NMDAmediated synaptic response in hippocampal neurons (Nelson et al, 2005), we examined expression levels after CIE withdrawal. We found that this effect persisted during the period Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, the corresponding adaptive changes in NMDA receptor remain unclear, especially in the cerebral cortex. NMDA receptor-mediated field excitatory postsynaptic potentials investigated in the CIE rat model were reported recently to result in a significant enhancement of NMDA receptor-mediated synaptic response to NMDA (Nelson et al, 2005). Mechanisms underlying these changes have not yet been reported.…”

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confidence: 99%

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Chronic Intermittent Ethanol Treatment Selectively Alters N-Methyl-d-aspartate Receptor Subunit Surface Expression in Cultured Cortical Neurons

2007

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A chronic intermittent ethanol (CIE) exposure regimen consists of repeated episodes of ethanol intoxication and withdrawal. CIE treatment has been reported to result in a significant enhancement of N-methyl-D-aspartate (NMDA) receptor-mediated synaptic responses in vivo, and trafficking of NMDA receptors is emerging a key regulatory mechanism that underlies the channel function. Therefore, in the present study, we examined the effects of CIE on NMDA receptor subunit surface expression. Cultured cortical neurons were exposed to 75 mM ethanol for 14 h followed by 10 h of withdrawal, repeated this cycle five times, and followed by 2 or 5 days of withdrawal. Surface-expressed NMDA receptor subunits and their endocytosis were measured by biotinylation and Western blots. CIE significantly increased NMDA receptor (NR) 1 and NR2B but not NR2A subunit surface expression after 5 days of treatment.However, CIE treatment did not reduce the NMDA receptor endocytosis. Quantification of immunocytochemistry confirmed CIE-induced increase in both the total number of NR1 and NR2B subunit clusters and their targeting to synaptic sites. It is noteworthy that this effect persisted even after ethanol withdrawal with a peak expression occurring between 0 and 2 days after withdrawal, and the expression on the plasma membrane was still at high levels after 5 days of withdrawal. In addition, this was accompanied by significant increases in postsynaptic density protein 95 clusters. Protein kinase A inhibitor completely reversed CIE-induced increase in NR1 and partially in NR2B surface level and a long-lasting effect. These changes may contribute to the development of ethanol-induced neurotoxicity and ethanol dependence.NMDA receptor mediates excitatory neurotransmission in the central nervous system and plays a central role in the function of excitatory synapses, which are important in neuronal development, memory formation, and many forms of synaptic plasticity. The level of NMDA receptor function at the synapse critically regulates brain function and cell survival. At synapses, it is believed that the appropriate clustering of this receptor at the postsynaptic membrane is critical for efficient synaptic transmission, and a dynamic balanced process of NMDA receptors is key to remaining constant at the surface level of receptors (Wenthold et al., 2003). Trafficking of NMDA receptor has emerged as a key regulatory mechanism that underlies channel function. Recent experimental evidence supports that NMDA receptors are quite mobile within neurons via endocytosis and lateral diffusion in the membrane (Rao and Craig, 1997;Tovar and Westbrook, 1999;Crump et al., 2001;Snyder et al., 2005). For example, long-term treatment with NMDA receptor antagonists leads to an increase in surface clusters of NMDA receptors and a shift to a more synaptic localization (Rao and Craig, 1997).The NMDA receptor system has emerged as an important site for the action of ethanol. Short-term ethanol exposure depresses NMDA receptor-activated ionic currents and...

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Section: Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Chronic Intermittent Ethanol Treatment Selectively Alters N-Methyl-d-aspartate Receptor Subunit Surface Expression in Cultured Cortical Neurons

2007

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“…Chronic ethanol administration has been observed to lead to supersensitivity of NMDA receptors (Nelson et al, 2005;Hendricson et al, 2007). One mechanism for the change of NMDA receptor sensitivity has been proposed to involve alterations of NMDA receptor subunits (Sheela Rani and Ticku, 2006), since relatively little change of NMDA receptor density was observed after chronic ethanol treatment (Tremwel et al, 1994;Rudolph et al, 1997;Freund and Anderson, 1999).…”

Section: Discussionmentioning

confidence: 99%

The effects of chronic ethanol administration on amygdala neuronal firing and ethanol withdrawal seizures

Feng

Faingold

2008

Neuropharmacology

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SummaryPhysical dependence on ethanol results in an ethanol withdrawal (ETX) syndrome including susceptibility to audiogenic seizures (AGS) in rodents after abrupt cessation of ethanol. Chronic ethanol administration and ETX induce functional changes of neurons in several brain regions, including the amygdala. Amygdala neurons are requisite elements of the neuronal network subserving AGS propagation during ETX induced by a subacute "binge" ethanol administration protocol. However, the effects of chronic ethanol administration on amygdala neuronal firing and ETX seizure behaviors are unknown. In the present study ethanol (5 g/kg) was administered intragastrically in Sprague-Dawley rats once daily for 28 days [chronic intermittent ethanol (CIE) protocol]. One week later the rats began receiving ethanol intragastrically 3 times daily for 4 days (binge protocol). Microwire electrodes were implanted prior to CIE or on the day after CIE ended day 29 to record extracellular action potentials in lateral amygdala (LAMG) neurons. The first dose of ethanol administered in the binge protocol following CIE treatment did not alter LAMG neuronal firing, which contrasts with firing suppression seen previously in the binge protocol alone. These data indicate that CIE induces neuroadaptive changes in the ETX network which reduce LAMG response to ethanol. LAMG neuronal responses to acoustic stimuli prior to AGS were significantly decreased during ETX as compared to those before ethanol treatment. LAMG neurons fired tonically throughout the tonic convulsions during AGS. CIE plus binge treatment resulted in a significantly greater mean seizure duration and a significantly elevated incidence of death than was seen previously with the binge protocol alone, indicating an elevated seizure severity following chronic ethanol administration.

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“…Acute and chronic effects of alcohol exposur e o n N M D A R s h a v e b e e n o b s e r v e d i n hippocampal brain slices in which resistance develops 5-15 min after exposure to ethanol (100 mM) (Miyakawa et al, 1997;Yaka et al, 2003;Nelson et al, 2005). However, the mechanisms of this resistance are not fully understood.…”

Section: Acute and Chronic Alcohol Exposurementioning

confidence: 99%

A Molecular Mechanism of Ethanol Dependence: The Influence of the Ionotropic Glutamate Receptor Activated by N-Methyl-D-Aspartate

Cordero¹,

Stab²,

Guillen³

et al. 2012

Addictions - From Pathophysiology to Treatment

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Chronic intermittent ethanol exposure enhances NMDA-receptor-mediated synaptic responses and NMDA receptor expression in hippocampal CA1 region

Cited by 71 publications

References 64 publications

Chronic Intermittent Ethanol Treatment Selectively Alters N-Methyl-d-aspartate Receptor Subunit Surface Expression in Cultured Cortical Neurons

Chronic Intermittent Ethanol Treatment Selectively Alters N-Methyl-d-aspartate Receptor Subunit Surface Expression in Cultured Cortical Neurons

The effects of chronic ethanol administration on amygdala neuronal firing and ethanol withdrawal seizures

A Molecular Mechanism of Ethanol Dependence: The Influence of the Ionotropic Glutamate Receptor Activated by N-Methyl-D-Aspartate

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